Although recent anti-smoking campaigns and legislation have achieved success in reducing the number of adult cigarette smokers, other populations have been not so positively affected. For instance, there continues to be high rates of nicotine use in adolescents as well as in various clinical populations, including those with schizophrenia or Attention- Deficit/Hyperactivity Disorder (ADHD). Despite substantial research, it remains unclear why nicotine use is high in these groups. Various theories have been proposed, including the notion that nicotine is used to alleviate dysfunctional reward systems and that nicotine is used to self-medicate for cognitive impairment. Nicotine has beneficial effects on functions such as attention and memory, lending support to the latter theory. However, little is known about the effects of nicotine and the role of nicotinic acetylcholine receptors in regulating inhibitory behavior. Deficits in inhibition are considered among the core impairments in ADHD and are also associated with schizophrenia. Likewise, normal adolescence is often characterized by impulsivity and inhibitory deficits. To fill this gap in the literature, the proposed experiments will determine how nicotine effects inhibition using an animal model of response inhibition that is analogous to inhibition tasks commonly used in research with humans. Our preliminary data indicate that nicotine specifically enhances the ability of rats to withhold a learned response, as has been observed in humans with ADHD. Thus, the first objective will be to determine which subtype(s) of nicotinic acetylcholine receptor mediates the beneficial effects of nicotine on inhibition. This will be done using pharmacological approaches in both normal rats and a strain of rats commonly used as a model of ADHD. The second objective is to determine the brain systems through which nicotine affects inhibition. These studies will use a combination of approaches consisting of selective cholinergic denervation of the prefrontal cortex or hippocampus, and treatment with nicotinic receptor subtype-specific compounds. Finally, the third objective is to test for sex differences in the effects of nicotine on inhibitory behavior. These final experiments are based on growing reports of sex differences in cognitive dysfunction in disorders such as ADHD and differences in smoking rates between males and females. Together, these results of the proposed studies will provide new insight into how nicotine affects inhibitory behavior and promote the development of enhanced smoking cessation and treatment regimens. PUBLIC HEALTH RELEVANCE: The proposed studies will provide new insight into how nicotine and nicotinic acetylcholine receptors modulate response inhibition. Deficits in inhibition are associated with various disorders that are characterized by high rates of nicotine abuse, including schizophrenia and Attention-Deficit/Hyperactivity Disorder (ADHD). A better understanding of the contribution of nicotinic cholinergic systems to inhibition will have direct bearing on efforts to reduce smoking in these and other populations. Indeed, cigarette smoking is the leading cause of preventable death and is linked to cancer and to other lung and cardiovascular diseases. Limiting nicotine use by adolescents (with ADHD for example) is particularly important given the potential negative effects of nicotine on the developing brain.